CN115925604A - 吡咯烷类新型脂质化合物、其制备方法、组合物及应用 - Google Patents
吡咯烷类新型脂质化合物、其制备方法、组合物及应用 Download PDFInfo
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- CN115925604A CN115925604A CN202111110832.5A CN202111110832A CN115925604A CN 115925604 A CN115925604 A CN 115925604A CN 202111110832 A CN202111110832 A CN 202111110832A CN 115925604 A CN115925604 A CN 115925604A
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Abstract
本发明公开了一种如式A所示的新型吡咯烷类化合物，或其异构体、或其N‑氧化物、或其药学可接受的盐、前药。还公开了上述吡咯烷类化合物的制备方法、组合物及应用。该类化合物作为阳离子脂质，适用于核酸递送的药物组合物，可实现更优的稳定性、pKa值和药物的细胞内递送效率，其中式A如下。
Description
技术领域
本发明提供新型阳离子脂质，其可用于与其他脂质组分(如中性脂质、类固醇和聚合物缀合的脂质)结合，以便形成一种核酸mRNA脂质纳米粒子组合物将一种或多种治疗剂和/或预防剂递送至哺乳动物细胞或器官和/或在哺乳动物细胞或器官中产生多肽的方法。除新型脂质外，本发明的脂质纳米粒子组合物还可以包括呈特定比例的一种或多种阳离子性和/或可离子化氨基脂质、包括多不饱和脂质在内的中性脂质、聚合物缀合的脂质、类固醇、和/或治疗剂和/或预防剂。
背景技术
生物活性物质如小分子药物、蛋白质和核酸的有效靶向递送提出了一个持久的医学难题。确切地说，将核酸递送至细胞因这些物种的相对不稳定性和低细胞渗透性而变得困难。因此，需要开发有助于将治疗剂和/或预防剂如核酸递送至细胞的方法和组合物。
经研究证明，利用含脂质的纳米颗粒组合物、脂质体和脂质体复合物作运输媒介，可有效地将生物活性物质如小分子药物、蛋白质和核酸运送至细胞和/或细胞内隔室中。这些组合物一般包含一种或多种"阳离子性"脂质，包括多不饱和脂质在内的中性脂质(如磷脂)、结构性脂质(如类固醇)和/或含聚乙二醇的脂质(聚合物缀合的脂质)。阳离子脂质包括如可容易地质子化的含胺脂质。
然而，在治疗环境中使用寡核苷酸目前面临着两个问题。第一，游离的RNA易于在血浆中核酸酶消化。第二，游离RNA进入存在相关翻译机制的细胞内隔室的能力受限。由阳离子脂质与其他脂质组分(如中性脂质、胆固醇、PEG、PEG化的脂质和寡核苷酸)形成的脂质纳米颗粒已用于阻止RNA在血浆中的降解并促进寡核苷酸的细胞摄取。
仍然有必要改进的用于递送寡核苷酸的阳离子脂质和脂质纳米颗粒。改进的脂质纳米颗粒会提供优化的药物递送，保护核酸不在血清中被降解和清除，其适于全身或局部递送，并且提供核酸的细胞内递送。另外，这些优选的脂质-核酸颗粒应当是耐受良好的，并且提供足够的治疗指数，使得在有效剂量的核酸下的患者治疗不会对患者产生不可接受的毒性和/或风险。本发明提供这些优点和相关的优点。
公开内容
本发明提供以下新型化合物和涉及这些化合物的方法：
一种如式A所示的吡咯烷类化合物，或其异构体、或其N-氧化物、或其药学可接受的盐、前药；
其中：
L1选自以下结构：-C-、-O(C＝O)-、-(C＝O)O-、-C(＝O)-、-O-、-S(O)X-、-S-S-、-C(＝O)S-、-SC(＝O)-、-N-C(＝O)-、-C(＝O)-N-，L2选自以下结构：-C-、-(C＝O)O-、-C(＝O)-、-S(O)X-、-C(＝O)S-、-C(＝O)-N-；
R1和R2各自独立地为C6-C24烷基或C6-C24烯基，所述的烃基链任意的被一个或多个酯键或醚键连接；
R3和R4各自独立地为C1-C12烷基或C1-C12烯基，或R3和R4彼此结合形成4至10元杂环，所述杂原子包括N、O、S中的一种或多种杂原子，所述杂环任选地被1-6个杂原子取代；
X为C、N、O、S、-S-S-；
M为C1-C12烷基或C1-C12烯基；
x为0、1或2。
在各个不同的实施方案中，所述化合物具有以下表1中所示的结构之一。
表一化合物列表
在一些实施方案中，提供了包含结构式(I)的化合物中的任一种或多种和治疗剂和/或预防剂的组合物。
在一些实施方案中，提供了包含结构(I)的化合物中的任一种或多种和治疗剂和/或预防剂的组合物。在一些实施方案中，所述组合物包含结构(I)的化合物中的任一种和治疗剂和/或预防剂以及一种或多种选自中性脂质、类固醇和聚合物缀合的脂质的赋形剂。其他药物可接受的赋形剂和/或载体也包括在组合物的各种实施方案内。
在一些实施方案中，中性脂质选自1，2-二硬脂酰基-sn-甘油-3-磷酸胆碱(DSPC)、1，2-二棕榈酰基-sn-甘油-3-磷酸胆碱(DPPC)、1，2-二肉豆寇基-sn-甘油-磷酸胆碱(DMPC)、1，2-二油酰基-sn-甘油-3-磷酸胆碱(DOPC)、1-棕榈酰基-2-油酰基-sn-甘油-3-磷酸胆碱(POPC)、1，2-二油酰基-sn-甘油-3-磷酸乙醇胺(DOPE)、鞘磷脂(SM)和其混合。在一些实施方案中，优选中性脂质为1，2-二硬脂酰基-sn-甘油-3-磷酸胆碱(DSPC)。
在一些实施方案中，类固醇选自胆固醇、粪固醇、谷固醇、麦角固醇、菜油固醇、豆固醇、菜籽固醇、番茄碱、熊果酸、α-生育酚和其混合。在一些实施方案中，优选类固醇为胆固醇。
在一些实施方案中，聚乙二醇化脂质为1,2-二肉豆蔻酰基-sn-甘油甲氧基聚乙二醇(PEG-DMG)。
在一些实施方案中，所述组合物比例以下范围：约10～60mol％所述化合物、约0～30mol％中性脂质、约10～55mol％类固醇和约0～10mol％聚合物缀合的脂质。
在一些前述组合物的实施方案中，治疗剂和/或预防剂包括核酸。其中核酸为RNA，其选自以下组成：siRNA、aiRNA、miRNA、dsRNA、shRNA、mRNA以及其混合物。在一些实施方案中，所述RNA选自mRNA。
在其他不同的实施方案中，本发明涉及向有需要的受试者施用治疗剂和/或预防剂的方法，该方法包括制备或提供上述组合物中的任一种并向受试者施用该组合物。
出于施用的目的，本发明的化合物(通常是脂质纳米颗粒与治疗剂和/或预防剂结合的形式)可以以原料药施用，或者可以配制为药物组合物。本发明的药物组合物包含结构(I)的化合物和一种或多种药物可接受的载体、稀释剂或赋形剂。结构(I)的化合物以有效形成脂质纳米颗粒并递送治疗剂和/或预防剂。本领域技术人员可以容易地确定适当的浓度和剂量。
本发明组合物的施用可以通过任何用于类似效用的试剂的可接受施用方式来进行。本发明的药物组合物可以配制成固体、半固体、液体或气体形式的制剂，例如片剂、胶囊、粉末、颗粒、软膏、溶液、悬浮液、栓剂、注射剂、吸入剂、凝胶、微球和气溶胶。施用这类药物组合物的典型途径包括，但不限于，口服、局部、经皮、吸入、胃肠外、舌下、口含、直肠、阴道和鼻内途径。本文使用的术语胃肠外包括皮下注射，静脉内、肌内、皮内、胸骨内注射或输注技术。配制本发明的药物组合物以便允许经过对受试者施用该组合物后其中含有的活性成分是生物可利用的。待向对象或患者施用的组合物是一个或多个剂量单位的形式，其中，片剂可以是单剂量单位，而本发明气溶胶形式的化合物的容器可以容纳多个剂量单位。制备这些剂型的现行的方法是己知的，或者对于本领域技术人员是显而易见的。在任何情况下，待施用的组合物将会含有治疗有效量的本发明化合物或其药物可接受的盐，以便根据本发明的教导治疗相关的疾病或病况。
本发明的药物组合物可以是固体或液体的形式。一方面，载体是微粒，使得组合物是片剂或粉末形式。载体可以是液体，此时组合物是口服糖浆或可注射液体或气溶胶，所述气溶胶适用于吸入施用。
当意图用于口服施用时，药物组合物优选为固体或液体形式，其中本文认为是固体或液体的形式包括半固体、半液体、悬浮液和凝胶形式。
作为用于口服施用的固体组合物，药物组合物可以配制成粉末、颗粒、压缩的片剂、丸剂、胶囊、咀嚼胶、薄片等形式。这类固体组合物通常将含有一种或多种惰性稀释剂或可食用载体。另外，可以存在以下的一种或多种:粘合剂，如明胶、纤维素等；赋形剂，如乳糖等；崩解剂，如海藻酸等；润滑剂，如硬脂酸镁等；助流剂，如硅胶等；甜味剂，如蔗糖或糖精；调昧剂，如薄荷等；以及着色剂。
当药物组合物是胶囊形式时，其可以含有上述类型材料之外的液体载体，如聚乙二醇或油。
药物组合物可以是液体的形式，如糖浆、溶液、乳液或悬浮液。作为两种实例，液体可以用于口服施用或用于注射递送。当意图用于口服施用时，优边的组合物含有，除本发明化合物之外的，甜味剂、防腐剂、染色/着色剂和增昧剂中的一种或多种。在通过注射施用的组合物中，可以包括表面活性剂、防腐剂、润湿剂、分散剂、悬浮剂、缓冲剂、稳定剂和等渗剂中的一种或多种。
本发明的液体药物组合物，不论其为溶液、悬浮液还是其他类似的形式，可以包括以下佐剂中的一种或多种:无菌稀释剂，如注射用水、盐水溶液、优选生理盐水、林格氏溶液、等渗氯化钠；不挥发性油类，如可用作溶剂或悬浮介质的合成的单甘酯或双甘酯，聚乙二醇、甘油、丙二醇或其他溶剂；抗菌剂，如尼泊金甲醋等；抗氧化剂，如抗坏血酸或亚硫酸氢钠；螯合剂，如乙二肢四乙酸；缓冲剂，如乙酸盐、拧棱酸盐或磷酸盐；以及用于调节张力的试剂，如氯化钠或葡萄糖；用作冷冻保护剂的试剂，如蔗糖或海藻糖。胃肠外制剂可以封装在玻璃或塑料制作的安瓿、一次性注射器或多剂量瓶中。生理盐水是优选的佐剂。可注射的药物组合物优选为无菌的。
本发明的药物组合物可以由可作为气溶胶施用的剂量单位组成。术语气溶胶用于表示从胶体性质的系统到由加压包装组成的系统的各种系统。可以通过液化气或压缩气来递送，或者通过分散活性成分的适合的泵系统来递送。本发明化合物的气溶胶可以以单相、双相系统或三相系统来递送，以便递送活性成分。气溶胶的递送包括必要的容器、活化剂、阀、子容器等，其在一起可以形成试剂盒。本领域技术人员不需过度实验即可确定优选的气溶胶。
本发明的药物组合物可以通过制药领域熟知的方法来制备。意图通过注射施用的药物组合物可以通过将本发明的脂质纳米颗粒与无菌的蒸馏水或其他载体结合成溶液来制备。可以加入表面活性剂以促进形成均匀的溶液或悬浮液。表面活性剂是与本发明化合物非共价地相互作用，以便促进所述化合物在水性递送系统中溶解或均匀悬浮的化合物。
本发明的组合物或其药物可接受的盐以治疗有效量施用，所述量将会根据多种因素变化，包括使用的具体治疗剂的活性；治疗剂的代谢稳定性和作用时长；受试者的年龄、体重、一般健康状况、性别和饮食；施用的方式和时间；排泄速率；药物组合；具体病例的严重性等。
本发明的组合物也可以在施用一种或多种其他治疗剂的同时、之前或之后施用。这类组合治疗包括施用本发明组合物和一种或多种另外的活性剂的单一药物剂量制剂，以及施用本发明组合物和各个在其自身单独药物剂量制剂中的活性剂。例如，本发明组合物和其他活性剂可以以单一口服剂量组合物(如片剂或胶囊)一起向受试者施用，或者各个试剂以不同的口服剂量制剂施用。当使用不同的剂量制剂时，本发明化合物和一种或多种另外的活性剂可以在基本同一时间施用，或者在相互交错的时间依次施用；应理解组合治疗包括所有的这些给药方案。
上述新型阳离子脂质化合物的结构修饰和设计，实现了更有优势的理化性质，包括更合适的pKa和更好的化学稳定性，用于mRNA纳米脂质体组合物，可实现对离子类核酸药物更有效结合并递送，同时其化学结构更稳定，便于合成和有利开发为药用辅料。
上述化合物和组合物的制备方法在下文描述，和/或在本领域已知。
本领域的技术人员将会认识到，在本文描述的方法中，中间化合物的官能团可能需要通过适合的保护基保护。这类官能团包括羟基、氨基和羧酸。用于羟基的适合的保护基包括三烷基甲硅烷基或二芳基烷基甲硅烷基、四氢呋喃基、苄基等。用于氨基的适合的保护基包括叔丁氧基羰基、苄氧基羰基等。用于羧酸的适合的保护基包括烃基、芳基或芳烃基酯。保护基可以根据标准技术添加或去除，所述标准技术是本领域技术人员已知的合本文中描述的。
本领域技术人员还将认识到，虽然本发明化合物的这类经保护的衍生物可以不由此具有药物活性，但其可以对哺乳动物施用并且之后在体内代谢形成具有药理活性的本发明化合物。这类衍生物因此可以被描述为“前药”。所以本发明化合物的前药包括在本发明的范围内。
此外，所有以游离碱或游离酸形式存在的本发明化合物可以根据本领域技术人员已知的方法用适当的无机或有机的碱或酸处理来转化为其药物可接受的盐。本发明化合物的盐可以通过标准技术转化为其游离碱或酸形成。
提供了以下实施例，其目的在于举例展示，并非限定。
以下实施例，除非另外指出，否则使用的所有溶剂和试剂都是商购得到并且以原样使用。
以下描述的程序可用于合成化合物1。
本文采用了以下缩写:
DIEA：二异丙基乙胺
HATU：2-(7-氮杂苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯
K2CO3:碳酸钾
DMF：N,N-二甲基甲酰胺
NaOH：氢氧化钠
THF：四氢呋喃
TBAB：四丁基溴化铵
具体实施方式
实施例1：
代表性路线
化合物CLPP：N-(二乙基胺)乙基)-1-十五羰基-4-十五氧基)吡咯烷酮-2-甲酰胺
1)中间体F的制备
室温下，将原料H(1g,4.32mmol)、G(1.51g,5.18mmol)和DMF(100ml)加入250ml四颈瓶中，搅拌溶解。加入K2CO3(0.78g,5.62mmol)，加热至80℃，搅拌反应4h，TLC检测反应完全。加入乙酸乙酯，有机相分别用水、碳酸氢钠、稀盐酸、水洗涤，Na2SO4干燥后，减压浓缩后，制得中间体F粗品，柱层析纯化，得到1.49g目标化合物，收率78％。
分子式：C25H47NO5
分子量:441.64
LC-MS:m/z 442[M+H]
1H NMR(DMSO-d6):δ(ppm)11.02(s,1H)4.25(t,1H,J＝3.5),3.50(m,2H)3.39(m,2H),3.05(m,1H),1.98(m,2H),1.40-1.47(m,11H),1.25-1.33(m,24H),0.99(m,3H)。
2)中间体D的制备
向100ml反应瓶中，加入中间体F(1.03g,2.34mmol)和N,N-二甲基甲酰胺(DMF)20mL，冰浴冷却，搅拌，≤5℃依次加入0.84g(6.5mmol)二异丙基乙胺(DIEA)、中间体N-取代胺(E,2.34mmol)和0.83g(2.6mmol)O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(HATU)，室温搅拌3h，TLC检测反应完全。搅拌下，将反应液倒入100g冰水中，继续搅拌0.5h，乙酸乙酯提取3次(30mL×3)，合并乙酸乙酯层，有机相依次水、盐酸、碳酸氢钠、食盐水洗涤，无水MgSO4干燥，减压蒸馏后，制得中间体C粗品，柱层析(石油醚:乙酸乙酯＝5:1洗脱)，得1.07g浅色油状物，收率85.01％。
分子式：C31H61N3O4
分子量：539.47
LC-MS:m/z 540[M+H]
1H NMR(DMSO-d6):δ(ppm)8.06(s,1H),4.27(t,1H,J＝3.5Hz),3.52(m,2H)3.40(m,2H),3.35(m,2H),3.02(t,1H，J＝3Hz),2.70(m，2H),2.30(m,4H),1.98(m,2H),1.40-1.47(m,11H),1.25-1.33(m,24H),1.02-0.99(m,9H)。
3)中间体C的制备
将(3.13g,5.8mmol)中间体C和30mL乙酸乙酯置于100mL的三颈瓶中，搅拌，冰水浴冷却，≤10℃，0.5h内滴加入2.5mL 33％HCl乙醇溶液(14.5mmol)，室温搅拌4h，TLC检测反应完全，水提取3次(30mL×3)，合并水层，水相用乙酸乙酯洗涤，水层加入30mL二氯甲烷，搅拌，加Na2CO3调pH至8-9，分层，水层用二氯甲烷提取2次(30ml×2)，合并二氯甲烷层，饱和食盐水洗3次，无水MgSO4干燥，过滤，减压浓缩后，制得中间体C粗品，经柱层析纯化，得油状物2.45g，收率96％。
分子式：C26H53N3O2
分子量:439.72
LC-MS:m/z 440[M+H]
1H NMR(DMSO-d6):δ(ppm)8.06(s,1H),4.27(t,1H,J＝3.5),3.52(m,2H)3.40(m,2H),3.35(m,2H),3.02(t,1H，J＝3),2.70(m，2H),2.30(m,4H),2.01(s,1H),1.98(m,2H),1.47(m,2H),1.25-1.33(m,24H),0.99(m,9H)。
4)化合物1的制备
向100ml反应瓶中，加入中间体C(1.03g,2.34mmol)和N,N-二甲基甲酰胺(DMF)20mL，冰浴冷却，搅拌，≤5℃依次加入0.84g(6.5mmol)二异丙基乙胺(DIEA)、中间体CLPP-6(2.34mmol)和0.83g(2.6mmol)O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(HATU)，室温搅拌3h，TLC检测反应完全。搅拌下，将反应液倒入100g冰水中，继续搅拌0.5h，乙酸乙酯提取3次(30mL×3)，合并乙酸乙酯层，有机相依次水、盐酸、碳酸氢钠、食盐水洗涤，无水MgSO4干燥，减压蒸馏后，制得化合物1粗品，柱层析(石油醚:乙酸乙酯＝5:1洗脱)，得1.4g浅黄色油状物，收率90％。
分子式：C41H81N3O3
分子量:664.10
LC-MS:m/z 665[M+H]
1H NMR(DMSO-d6):δ(ppm)8.06(s,1H),4.27(t,1H,J＝3.5),3.52(m,2H)3.40(m,2H),3.35(m,2H),3.02(t,1H，J＝3),2.70(m，2H),2.36(t,2H,J＝6)，2.30(m,4H),2.20(m,2H),1.60(m,2H),1.47(m,2H),1.25-1.33(m,42H),0.99(m,12H)。
实例2化合物2-己基葵酸6-溴己基酯(C1)的合成
向500ml反应瓶中，加入商业可得的2-己基葵酸(10g，35.15mmol)和四氢呋喃(THF)200mL，依次加入8.27g(45.70mmol)6溴己醇、6.3g碳酸钾，升温到68℃搅拌8h，TLC检测反应完全。搅拌下，乙酸乙酯提取3次(30mL×3)，合并乙酸乙酯层，有机相依次水、盐酸、碳酸氢钠、食盐水洗涤，无水MgSO4干燥，减压蒸馏后，制得侧链2-辛基葵酸6-溴己基酯粗品，柱层析(石油醚:乙酸乙酯＝10:1洗脱)，得12.56g 2-己基葵酸6-溴己基酯黄色油状物，收率80％。
分子式：C22H43BrO2
分子量:419.54
LC-MS:m/z 420[M+H]
1H NMR(DMSO-d6):4.13(m,2H,),3.52(m,2H)2.13(m,1H),1.82(m,2H),1.60(m,6H),1.47(m,2H),1.29(m,16H),0.90(m,6H)。
实例3化合物6-(十七基-9氧基)-6-羰基己酸(C2)的合成
向500ml反应瓶中，加入商业可得的9-十七醇(10g,38.99mmol)和N,N-二甲基甲酰胺(DMF)100mL，依次加入5.7g(38.99mmol)己二酸、氢氧化钠(2.34g，58.49mmol)，升温到80℃搅拌6h，TLC检测反应完全。搅拌下，乙酸乙酯提取3次(30mL×3)，合并乙酸乙酯层，有机相依次水、碳酸氢钠，盐酸、食盐水洗涤，无水MgSO4干燥，减压蒸馏后，制得侧链6-(十七基-9氧基)-6-羰基己酸粗品，柱层析(石油醚:乙酸乙酯＝1:1洗脱)，得9g 6-(十七基-9氧基)-6-羰基己酸黄色油状物，收率60.03％。
分子式：C23H44O4
分子量:384.60
LC-MS:m/z 385[M+H]
1H NMR(DMSO-d6):11.87(s，1H),4.47(m,1H),2.32(m,2H),2.21(m,2H),1.64(m,2H),1.52(m,2H),1.49(m,4H),1.29(m,4H),1.26(m,20H),0.90(m,6H)。
实例4化合物6-溴己基-9-十七醚(C3)的合成
向500ml反应瓶中，加入商业可得的9-十七醇(10g,38.99mmol)和N,N-二甲基甲酰胺(DMF)50mL，依次加入5.7g(38.99mmol)6-溴己醇、氢氧化钠(2.34g，58.49mmol)和2.34g水，加入0.3当量TBAB,升温到60℃搅拌12h，TLC检测反应完全。搅拌下，乙酸乙酯提取3次(30mL×3)，合并乙酸乙酯层，有机相依次水、碳酸氢钠，盐酸、食盐水洗涤，无水MgSO4干燥，减压蒸馏后，制得侧链6-溴己基-9-十七醚粗品，柱层析(石油醚:乙酸乙酯＝20:1洗脱)，得11..4g 6-(十七基-9氧基)-6-羰基己酸黄色油状物，收率70％。
分子式：C23H47BrO
分子量:419.53
LC-MS:m/z 420[M+H]
1H NMR(DMSO-d6):3.52(m,2H),3.35(m,2H),3.10(m,1H),1.82(m,2H),1.52(m,2H),1.49(m,2H),1.38(m,4H),1.29(m,6H),1.26(m,20H),0.90(m,6H)。
通过类似于实施列1、2、3、4的合成方法制备实施列2到60的化合物。
实例5化合物2的合成
通过类似于实施列1的合成方法制备得到淡黄色化合物2
分子式：C42H83N3O3
分子量：678.13
LC-MS:m/z 679[M+H]
1H NMR(DMSO-d6):δ(ppm)8.06(s,1H),4.27(t,1H,J＝3.5Hz),3.52(m,2H),3.40(m,2H),3.35(m,2H),3.02(t,1H，J＝3Hz),2.70(m,2H),2.36(m,6H),2.30(m,4H),2.20(m,2H),1.60(m,2H),1.47(m,2H),1.25-1.33(m,46H),0.99(m,12H)。
实例6化合物3的合成
通过类似于实施列1的合成方法制备得到淡黄色化合物3
分子式：C44H87N3O3
分子量：706.18
LC-MS:m/z 707[M+H]
1H NMR(DMSO-d6):δ(ppm)8.06(s,1H),4.27(t,1H,J＝3.5),3.52(m,2H),3.40(m,2H),3.35(m,2H),3.02(t,1H,J＝3),2.70(m,2H),2.36(m,6H),2.30(m,6H),2.20(m,2H),1.60(m,2H),1.47(m,2H),1.25-1.33(m,50H),0.99(m,12H)。
实例7化合物4的合成
通过类似于实施列1的合成方法制备得到淡黄色化合物4
分子式：C44H83N3O3
分子量：702.15
LC-MS:m/z 703[M+H]
1H NMR(DMSO-d6):δ(ppm)8.06(s,1H),5.60(d,2H,J＝2.6Hz),5.44(m,2H),54.27(t,1H,J＝3.5),3.52(m,2H),3.40(m,2H),3.35(m,2H),3.02(t,1H，J＝3),2.70(m，2H),2.65(m,2H),2.36(t,2H,J＝6),2.30(m,4H),2.20(m,2H),1.60(m,2H),1.47(m,2H),1.25-1.33(m,36H),0.99(m,12H)。
实例8化合物5的合成
通过类似于实施列1的合成方法制备得到淡黄色化合物5
分子式：C44H89N3O2
分子量：691.70
LC-MS:m/z 692[M+H]
1H NMR(DMSO-d6):δ(ppm)8.06(s,1H),3.37(m,2H),3.30(m,2H)3.23(m,1H),2.63(m,2H),2.44(m,4H),2.36(m，4H),1.47(m,2H),1.40(m,2H),1.25-1.33(m,48H),0.99(m,12H)。
实例9化合物6的合成
通过类似于实施列1的合成方法制备得到淡黄色化合物6
分子式：C41H83N3O2
分子量：650.12
LC-MS:m/z 651[M+H]
1H NMR(DMSO-d6):δ(ppm)8.06(s,1H),3.37(m,2H),3.30(m,2H)3.23(m,1H),2.63(m,2H),2.44(m,4H),2.36(m，4H),1.47(m,2H),1.40(m,2H),1.25-1.33(m,42H),0.99(m,12H)。
实例10化合物7的合成
通过类似于实施列1的合成方法制备得到淡黄色化合物7
分子式：C44H87N3O3
分子量：706.18
LC-MS:m/z 707[M+H]
1H NMR(DMSO-d6):δ(ppm)8.06(s,1H),4.46(t,1H,J＝5),3.62(m,2H),3.40(m,2H),3.35(m,2H),3.02(t,1H，J＝3),2.70(m，2H),2.45(m，1H),2.36(t,2H),2.30(m,4H),2.20(m,2H),1.5-1.25(m,54H),0.99(m,12H)。
实例11化合物8的合成
通过类似于实施列1的合成方法制备得到淡黄色化合物8
分子式：C32H63N3O3
分子量：537.93
LC-MS:m/z 540[M+H]
1H NMR(DMSO-d6):δ(ppm)8.06(s,1H),4.46(t,1H,J＝5),3.62(m,2H),3.40(m,2H),3.35(m,2H),3.02(t,1H，J＝3),2.70(m，2H),2.45(m，1H),2.36(t,2H),2.30(m,4H),2.20(m,2H),1.5-1.25(m,32H),0.99(m,9H)。
实例12化合物9的合成
通过类似于实施列1和实施列2的合成方法制备得到淡黄色化合物9
分子式：C48H95N3O4
分子量：778.34
LC-MS:m/z 779[M+H]
1H NMR(DMSO-d6):δ(ppm)8.06(s,1H),4.46(t,1H,J＝5),3.80(m,2H),3.62(m,2H),3.40(m,2H),3.35(m,2H),3.02(t,1H，J＝3),2.70(m，2H),2.45(m,1H),2.36(t,2H,J＝6),2.30(m,4H),2.20(m,2H),1.5-1.25(m,50H),0.90(m,15H)。
实例13化合物10的合成
通过类似于实施列1和实施列3的合成方法制备得到黄色化合物10
分子式：C47H91N3O5
分子量：778.32
LC-MS:m/z 779[M+H]
1H NMR(DMSO-d6):δ(ppm)8.06(s,1H),4.46(t,1H,J＝5),3.80(m,2H),3.62(m,2H),3.40(m,2H),3.35(m,2H),3.02(t,1H,J＝3),2.70(m，2H),2.45(m,1H),2.36(t,2H,J＝6),2.30(m,4H),2.20(m,2H),1.5-1.25(m,50H),0.99(m,15H)。
实例14化合物11的合成
通过类似于实施列1和实施列4的合成方法制备得到淡黄色化合物11
分子式：C49H95N3O5
分子量：806.32
LC-MS:m/z 807[M+H]
1H NMR(DMSO-d6):δ(ppm)8.06(s,1H),3.40(t,1H,J＝4.2),3.35(m,4H),3.30(m,3H),3.10(m,1H),2.65(m,2H),2.45(m,8H),1.52(m,2H)，1.44(m,6H),1.38(m,6H),1.29(m,6H),1.26(m,40H),0.90(m,15H)。
实例15化合物12的合成
通过类似于实施列1和实施列4的合成方法制备得到淡黄色化合物12
分子式：C57H115N3O4
分子量：906.56
LC-MS:m/z 907[M+H]
1H NMR(DMSO-d6):δ(ppm)8.06(s,1H),3.40(t,1H,J＝4.2),3.35(m,6H),3.30(m,3H),3.10(m,2H),2.65(m,2H),2.45(m,8H),1.52(m,4H),1.44(m,8H),1.38(m,10H),1.29(m,10H),1.26(m,40H),0.90(m,18H)。
实例16化合物13的合成
通过类似于实施列2，4的合成方法制备得到黄色化合物13
分子式：C55H107N3O6
分子量：906.53
LC-MS:m/z 907[M+H]
1H NMR(DMSO-d6):δ(ppm)8.06(s,1H),4.76(t,1H,J＝6.8Hz),4.47(m,1H),3.35(m,2H),3.30(m,3H),3.10(m,1H),2.72(t,2H,J＝2.9Hz),2.45(m,8H),2.30(m,4H),2.20(d,2H,J＝1.3Hz),1.64(m,4H),1.50(m,8H),1.38(m,4H),1.29(m,10H),1.26(m,36H)0.90(m,18H)。
实例17化合物14的合成
通过类似于实施列1，2，4的合成方法制备得到黄色化合物14
分子式：C56H111N3O5
分子量：906.57
LC-MS:m/z 907[M+H]
1H NMR(DMSO-d6):δ(ppm)8.06(s,1H),4.13(t,2H,J＝5.2Hz),3.39(t,1H,J＝3.7Hz),3.35(m,4H),3.30(m,3H),3.10(m,1H),2.60(t,2H,J＝1.3Hz),2.45(m,8H),2.20(m,3H),1.60(m,6H),1.50(m,2H),1.43(m,8H),1.38(m,6H),1.29(m,10H),1.26(m,36H),0.90(m,18H)。
实例18化合物15的合成
通过类似于实施列1，4的合成方法制备得到黄色化合物15
分子式：C50H101N3O4
分子量：806.41
LC-MS:m/z 807[M+H]
1H NMR(DMSO-d6):δ(ppm)8.06(s,1H),4.76(t,1H,J＝7.9Hz),3.35(m,2H),3.30(m,3H),3.10(m,1H),2.70(t,2H,J＝3.1Hz),2.45(m,8H),2.20(m,3H),1.60(m,4H),1.50(m,2H),1.43(m,2H),1.38(m,6H),1.29(m,10H),1.26(m,36H),0.90(m,18H)。
实例19化合物16的合成
通过类似于实施例1，4的合成方法制备得到黄色化合物16
分子式：C50H101N3O3
分子量：792.38
LC-MS:m/z 800[M+H]
1H NMR(DMSO-d6):δ(ppm)8.06(s,1H),3.39(t,1H,J＝4.3Hz),3.35(m,4H),3.30(m,3H),3.10(m,1H),2.70(t,2H,J＝3.1Hz),2.45(m,8H),2.20(d,2H,J＝2.3Hz),1.50(m,2H),1.43(m,6H),1.38(m,6H),1.29(m,8H),1.26(m,42H),0.90(m,15H)。
实例20化合物17的合成
通过类似于实施例1，4的合成方法制备得到黄色化合物17
分子式：C49H97N3O4
分子量：792.33
LC-MS:m/z 793[M+H]
1H NMR(DMSO-d6):δ(ppm)8.06(s,1H),4.76(t,1H,J＝6.8Hz),3.35(m,2H),3.30(m,3H),3.10(m,1H),2.70(t,2H,J＝3.1Hz),2.45(m,8H),2.35(m,2H),2.20(d,2H,J＝2.3Hz),1.66(m,2H),1.50(m,2H),1.43(m,2H),1.38(m,8H),1.29(m,6H),1.26(m,40H),0.90(m,15H)。
实例21化合物18的合成
通过类似于实施例1，4的合成方法制备得到黄色化合物18
分子式：C52H105N3O3
分子量：820.43
LC-MS:m/z 821[M+H]
1H NMR(DMSO-d6):δ(ppm)8.06(s,1H),3.39(t,1H,J＝4.3Hz),3.35(m,4H),3.30(m,3H),3.10(m,1H),2.70(t,2H,J＝3.1Hz),2.45(m,8H),2.20(d,2H,J＝2.3Hz),1.50(m,2H),1.43(m,6H),1.38(m,6H),1.29(m,8H),1.26(m,48H),0.90(m,15H)。
实例22化合物19的合成
通过类似于实施例1，4的合成方法制备得到黄色化合物19
分子式：C52H105N3O3
分子量：820.43
LC-MS:m/z 821[M+H]
1H NMR(DMSO-d6):δ(ppm)8.06(s,1H),4.76(t,1H,J＝6.8Hz),3.35(m,2H),3.30(m,3H),3.10(m,1H),2.70(t,2H,J＝3.1Hz),2.45(m,8H),2.35(m,2H),2.20(d,2H,J＝2.3Hz),1.66(m,2H),1.50(m,2H),1.43(m,2H),1.38(m,8H),1.29(m,6H),1.26(m,46H),0.90(m,15H)。
实例23化合物20的合成
通过类似于实施例1，4的合成方法制备得到黄色化合物20
分子式：C50H98N2O4
分子量：791.34
LC-MS:m/z 792[M+H]
1H NMR(DMSO-d6):δ(ppm)4.18(t,2H,J＝9.2Hz),3.40(t,1H，J＝4.2),3.35(m,4H),3.21(t,1H,J＝6.2Hz),3.10(m,1H),2.93(m,2H),2.65(d,2H,J＝2.5HZ),2.45(m,6H),1.52(m,6H),1.44(m,6H),1.38(m,8H),1.29(m,8H),1.26(m,40H),0.90(m,9H)。
实例24化合物21的合成
通过类似于实施例1，4的合成方法制备得到黄色化合物21
分子式：C49H99N3O5
分子量：810.35
LC-MS:m/z 811[M+H]
1H NMR(DMSO-d6):δ(ppm)8.06(s,1H),4.18(s,2H),3.40(m,5H,),3.35(m,4H),3.30(m,3H),3.10(m,1H),2.65(d,2H,J＝2.5HZ),2.59(m,4H),2.45(m,4H),2.10(d,1H,J＝3.3Hz),1.85(d,1H,J＝3.8Hz)1.52(m,2H),1.44(m,6H),1.38(m,6H),1.29(m,8H),1.26(m,44H),0.90(m,9H)。
实例25化合物22的合成
通过类似于实施例1，4的合成方法制备得到黄色化合物22
分子式：C50H99N3O4
分子量：806.36
LC-MS:m/z 807[M+H]
1H NMR(DMSO-d6):δ(ppm)4.18(s,2H),3.40(t,1H,J＝4.1Hz),3.35(m,4H),3.30(m,1H),3.18(t,1H,J＝3.2Hz),3.10(m,1H),2.98(t,2H,J＝3.35Hz),2.65(d,1H,J＝2.5HZ),2.36(d,1H,J＝2.83Hz),2.44(m,2H),2.30(m,8H)2.14(s,3H),1.52(m,2H),1.44(m,6H),1.38(m,6H),1.29(m,8H),1.26(m,40H),0.90(m,9H)。
实例26化合物23的合成
通过类似于实施例1，4的合成方法制备得到黄色化合物23
分子式：C49H96N2O5
分子量：793.32
LC-MS:m/z 794[M+H]
1H NMR(DMSO-d6):δ(ppm)4.18(s,2H),3.58(m,4H),3.40(t,1H,J＝4.1Hz),3.35(m,4H),3.30(m,1H),3.18(t,1H,J＝3.2Hz),3.10(m,1H),2.98(t,2H,J＝3.35Hz),2.65(d,1H,J＝2.5HZ),2.52(m,4H),2.45(m,2H)2.36(d,1H,J＝2.83Hz),2.17(d,1H,J＝1.82Hz),2.03(d,1H,J＝1.56Hz),1.52(m,2H),1.44(m,6H),1.38(m,6H),1.29(m,8H),1.26(m,40H),0.90(m,9H)。
实例27化合物24的合成
通过类似于实施例1，4的合成方法制备得到黄色化合物24
分子式：C49H96N2O4
分子量：777.32
LC-MS:m/z 778[M+H]
1H NMR(DMSO-d6):δ(ppm)4.23(s,2H),3.40(t,1H,J＝4.1Hz),3.35(m,4H),3.30(m,1H),3.18(t,1H,J＝3.2Hz),3.10(m,1H),2.98(t,2H,J＝3.35Hz),2.65(d,1H,J＝2.5HZ),2.52(m,4H),2.36(d,1H,J＝2.83Hz),2.17(d,1H,J＝1.87Hz),2.00(d,1H,J＝1.72Hz),1.70(m,4H),1.52(m,2H),1.44(m,6H),1.38(m,6H),1.29(m,8H),1.26(m,40H),0.90(m,9H)。
实例28化合物25的合成
通过类似于实施例1，4的合成方法制备得到黄色化合物25
分子式：C48H96N2O4
分子量：765.31
LC-MS:m/z 766M+H]
1H NMR(DMSO-d6):δ(ppm)4.10(s,2H),3.40(t,1H,J＝4.1Hz),3.35(m,4H),3.30(m,1H),3.18(t,1H,J＝3.2Hz),3.10(m,1H),2.65(d,1H,J＝2.5HZ),2.36(d,1H,J＝2.83Hz),2.32(m,2H),2.17(m,6H),,1.70(m,2H),1.52(m,2H),1.44(m,6H),1.38(m,6H),1.29(m,8H),1.26(m,40H)0.90(m,9H)。
实例29化合物26的合成
通过类似于实施例1，4的合成方法制备得到黄色化合物26
分子式：C57H115N3O6
分子量：938.56
LC-MS:m/z 939[M+H]
1H NMR(DMSO-d6):δ(ppm)8.06(s,1H),4.52(s,2H),3.45(m,4H),3.40(t,1H,J＝4.1Hz),3.35(m,6H),3.30(m,3H),3.10(m,2H),2.65(d,1H,J＝2.5HZ),2.58(m,4H),2.46(m,4H),2.36(d,1H,J＝2.83Hz),2.32(m,2H),2.10(d,1H,J＝3.8Hz),1.95(d,1H,J＝3.01Hz),1.52(m,4H),1.44(m,8H),1.38(m,8H),1.29(m,10H),1.26(m,40H),0.90(m,12H)。
实例30化合物27的合成
通过类似于实施例1，4的合成方法制备得到黄色化合物27
分子式：C56H112N2O5
分子量：893.52
LC-MS:m/z 894[M+H]
1H NMR(DMSO-d6):δ(ppm)4.18(t,2H,J＝2.3Hz),3.45(t,1H,J＝3.3Hz),3.35(m,6H),3.30(m,3H),3.10(m,2H),2.65(d,1H,J＝2.5HZ),2.38(m,2H),2.36(d,1H,J＝2.83Hz),2.15(s,6H),2.10(d,1H,J＝3.8Hz),1.95(d,1H,J＝3.01Hz),1.68(m,2H),1.52(m,4H),1.44(m,8H),1.38(m,8H),1.29(m,10H),1.26(m,40H)0.90(m,12H)。
实例31化合物28的合成
通过类似于实施例1，4的合成方法制备得到黄色化合物28
分子式：C58H114N2O5
分子量：919.56
LC-MS:m/z 920[M+H]
1H NMR(DMSO-d6):δ(ppm)4.18(t,2H,J＝2.3Hz),3.45(t,1H,J＝3.3Hz),3.35(m,6H),3.30(m,3H),3.10(m,2H),2.97(m,2H),2.65(d,1H,J＝2.5HZ),2.46(m,4H),2.38(m,2H),2.36(d,1H,J＝2.83Hz),2.10(d,1H,J＝3.8Hz),1.95(d,1H,J＝3.01Hz),1.52(m,4H),1.47(m,4H),1.44(m,8H),1.38(m,10H),1.29(m,10H),1.26(m,40H)0.90(m,12H)。
实例32化合物29的合成
通过类似于实施例1，4的合成方法制备得到黄色化合物29
分子式：C58H114N2O6
分子量：935.56
LC-MS:m/z 936[M+H]
1H NMR(DMSO-d6):δ(ppm)5.52(s,1H),4.18(t,2H,J＝2.3Hz),4.01(m,1H),3.45(t,1H,J＝3.3Hz),3.35(m,6H),3.20(t,1H,J＝6.7Hz),3.10(m,2H),2.97(m,2H),2.65(d,1H,J＝2.5HZ),2.45-2.53(m,6H),2.36(d,1H,J＝2.83Hz),2.10(d,1H,J＝3.8Hz),1.99(d,1H,J＝3.6Hz),1.82(m,4H),1.52(m,4H),1.44(m,8H),1.38(m,10H),1.29(m,10H),1.26(m,40H)0.90(m,12H)。
实例33化合物30的合成
通过类似于实施例1，4的合成方法制备得到黄色化合物30
分子式：C57H112N2O5
分子量：905.53
LC-MS:m/z 906[M+H]
1H NMR(DMSO-d6):δ(ppm)4.18(t,2H,J＝2.3Hz),3.45(t,1H,J＝3.3Hz),3.35(m,6H),3.20(t,1H,J＝6.7Hz),3.10(m,2H),2.97(m,2H),2.65(d,1H,J＝2.5HZ),2.53(m,4H),2.45(m,2H),2.36(d,1H,J＝2.83Hz),2.10(d,1H,J＝3.8Hz),1.99(d,1H,J＝3.6Hz),1.69(m,4H),1.52(m,4H),1.44(m,8H),1.38(m,10H),1.29(m,10H),1.26(m,40H)0.90(m,12H)。
实例34化合物31的合成
通过类似于实施例1，4的合成方法制备得到黄色化合物31
分子式：C58H115N3O5
分子量：934.57
LC-MS:m/z 935[M+H]
1H NMR(DMSO-d6):δ(ppm)4.18(t,2H,J＝2.3Hz),3.45(t,1H,J＝3.3Hz),3.35(m,6H),3.20(t,1H,J＝6.7Hz),3.10(m,2H),2.97(m,2H),2.65(d,1H,J＝2.5HZ),2.53(m,4H),2.45(m,2H),2.36(d,1H,J＝2.83Hz),2.30(m,8H),2.20(d,1H,J＝3.8Hz),2.15(s,3H),1.99(d,1H,J＝3.6Hz),1.52(m,4H),1.44(m,8H),1.38(m,10H),1.29(m,10H),1.26(m,40H),0.90(m,12H)。
实例35化合物32的合成
通过类似于实施例1，4的合成方法制备得到黄色化合物32
分子式：C50H99N3O6
分子量：838.41
LC-MS:m/z 839[M+H]
1H NMR(DMSO-d6):δ(ppm)8.06(s,1H),4.76(t,1H,J＝7.9Hz),4.52(s,2H),3.48(m,4H),3.35(m,2H),3.30(m,3H),3.10(m,1H),2.70(d,2H,J＝3.1Hz),2.62(m,4H),2.45(m,4H),2.20(m,3H),1.60(m,4H),1.50(m,2H),1.43(m,2H),1.38(m,6H),1.29(m,10H),1.26(m,36H),0.90(m,12H)。
实例36化合物33的合成
通过类似于实施例1，4的合成方法制备得到黄色化合物33
分子式：C49H96N2O5
分子量：793.37
LC-MS:m/z 794[M+H]
1H NMR(DMSO-d6):δ(ppm)4.76(t,1H,J＝7.9Hz),4.12(m,2H),3.35(m,2H),3.20(m,1H),3.10(m,1H),2.70(d,2H,J＝3.1Hz),2.45(m,4H),2.20(m,7H),2.31(m,2H),1.70(m,6H),1.50(m,6H),1.43(m,2H),1.38(m,8H),1.29(m,10H),1.26(m,36H),0.90(m,12H)。
实例37化合物34的合成
通过类似于实施例1，4的合成方法制备得到黄色化合物34
分子式：C48H94N2O5
分子量：793.37
LC-MS:m/z 794[M+H]
1H NMR(DMSO-d6):δ(ppm)4.76(t,1H,J＝7.9Hz),4.12(m,2H),3.35(m,2H),3.20(m,1H),3.10(m,1H),2.70(d,2H,J＝3.1Hz),2.45(m,4H),2.20(m,7H),2.31(m,2H),1.70(m,6H),1.50(m,6H),1.43(m,2H),1.38(m,8H),1.29(m,8H),1.26(m,36H),0.90(m,12H)。
实例38化合物35的合成
通过类似于实施例1，4的合成方法制备得到黄色化合物35
分子式：C44H86N2O5
分子量：723.18
LC-MS:m/z 724[M+H]
1H NMR(DMSO-d6):δ(ppm)4.76(t,1H,J＝7.9Hz),4.12(m,2H),3.35(m,2H),3.20(m,1H),3.10(m,1H),2.70(d,2H,J＝3.1Hz),2.45(m,4H),2.20(m,7H),2.31(m,2H),1.70(m,6H),1.50(m,6H),1.43(m,2H),1.38(m,8H),1.29(m,10H),1.26(m,34H),0.90(m,12H)。
实例39化合物36的合成
通过类似于实施例1，4的合成方法制备得到黄色化合物36
分子式：C51H88N2O5
分子量：819.41
LC-MS:m/z 820[M+H]
1H NMR(DMSO-d6):δ(ppm)4.76(t,1H,J＝7.9Hz),4.12(m,2H),3.35(m,2H),3.20(m,1H),3.10(m,1H),2.97(m,2H),2.70(d,2H,J＝3.1Hz),2.45(m,4H),2.20(m,1H),2.31(m,2H),1.50(m,2H),1.43(m,2H),1.38(m,8H),1.29(m,10H),1.26(m,36H),0.90(m,12H)。
实例40化合物37的合成
通过类似于实施例1，4的合成方法制备得到黄色化合物37
分子式：C50H96N2O6
分子量：821.38
LC-MS:m/z 822[M+H]
1H NMR(DMSO-d6):δ(ppm)4.76(t,1H,J＝7.9Hz),4.12(m,2H),3.59(m,4H),3.35(m,2H),3.20(m,1H),3.10(m,1H),2.97(m,2H),2.70(d,2H,J＝3.1Hz),2.45(m,4H),2.20(m,1H),2.31(m,2H),1.50(m,2H),1.43(m,2H),1.38(m,6H),1.29(m,10H),1.26(m,36H),0.90(m,12H)。
实例41化合物38的合成
通过类似于实施例1，4的合成方法制备得到黄色化合物38
分子式：C49H94N2O6
分子量：835.41
LC-MS:m/z 836[M+H]
1H NMR(DMSO-d6):δ(ppm)4.76(t,1H,J＝7.9Hz),4.49(s,1H),4.20(m,2H),3.59(m,1H),3.35(m,2H),3.20(m,1H),3.10(m,1H),2.97(m,2H),2.70(d,2H,J＝3.1Hz),2.45(m,6H),2.20(m,1H),2.31(m,2H),1.77(m,4H),1.50(m,2H),1.43(m,2H),1.38(m,6H),1.29(m,10H),1.26(m,36H),0.90(m,12H)。
实例42化合物39的合成
通过类似于实施例1，4的合成方法制备得到黄色化合物39
分子式：C50H96N2O5
分子量：805.38
LC-MS:m/z 806[M+H]
1H NMR(DMSO-d6):δ(ppm)4.76(t,1H,J＝7.9Hz),4.20(m,2H),3.35(m,2H),3.20(m,1H),3.10(m,1H),2.97(m,2H),2.70(d,2H,J＝3.1Hz),2.45(m,6H),2.20(m,1H),2.31(m,2H),1.71(m,4H),1.50(m,2H),1.43(m,2H),1.38(m,6H),1.29(m,10H),1.26(m,36H),0.90(m,12H)。
实例43化合物40的合成
通过类似于实施例1，4的合成方法制备得到黄色化合物40
分子式：C51H99N3O5
分子量：834.42
LC-MS:m/z 835[M+H]
1H NMR(DMSO-d6):δ(ppm)4.76(t,1H,J＝7.9Hz),4.20(m,2H),3.35(m,2H),3.20(m,1H),3.10(m,1H),2.97(m,2H),2.70(d,2H,J＝3.1Hz),2.45(m,2H),2.31(m,2H),2.29(m,8H),2.18(m,1H),2.14(s,3H),1.50(m,2H),1.43(m,2H),1.38(m,6H),1.29(m,10H),1.26(m,36H),0.90(m,12H)。
实例44化合物41的合成
通过类似于实施例1，2，4的合成方法制备得到黄色化合物41
分子式：C56H111N3O7
分子量：938.57
LC-MS:m/z 938[M+H]
1H NMR(DMSO-d6):δ(ppm)4.20(s,2H),4.18(m,2H),4.15(m,2H),3.46(t,1H,J＝3.2Hz),3.43(m,4H),3.35(m,4H),3.20(m,3H),3.10(m,1H),2.62(d,2H,J＝2.1Hz),2.57(m,4H),2.45(m,4H),2.18(m,1H),2.14(d,2H,J＝3.5Hz),1.62(m,6H),1.50(m,2H),1.43(m,8H),1.38(m,6H),1.29(m,10H),1.26(m,36H),0.90(m,12H)。
实例45化合物42的合成
通过类似于实施例1，2，4的合成方法制备得到黄色化合物42
分子式：C57H110N2O7
分子量：935.51
LC-MS:m/z 936[M+H]
1H NMR(DMSO-d6):δ(ppm)4.72(s,1H),4.18(m,2H),4.15(m,2H),3.46(t,1H,J＝3.2Hz),3.72(m,1H),3.35(m,4H),3.20(m,3H),3.10(m,1H),2.62(d,2H,J＝2.1Hz),2.57(m,4H),2.45(m,6H),2.18(m,1H),2.14(d,2H,J＝3.5Hz),1.82(m,4H),1.62(m,6H),1.50(m,2H),1.43(m,8H),1.38(m,6H),1.29(m,10H),1.26(m,36H)0.90(m,12H)。
实例46化合物43的合成
通过类似于实施例1，2，4的合成方法制备得到黄色化合物43
分子式：C57H111N3O6
分子量：934.58
LC-MS:m/z 963[M+H]
1H NMR(DMSO-d6):δ(ppm)4.33(m,2H),4.15(m,2H),3.46(t,1H,J＝3.2Hz),3.35(m,4H),3.20(m,3H),3.10(m,1H),2.97(m,2H),2.62(d,2H,J＝2.1Hz),2.45(m,2H),2.29(m,8H),2.18(m,4H),2.14(d,2H,J＝3.5Hz),1.62(m,6H),1.50(m,2H),1.43(m,8H),1.38(m,6H),1.29(m,10H),1.26(m,36H),0.90(m,12H)。
实例47化合物44的合成
通过类似于实施例1，2，4的合成方法制备得到黄色化合物44
分子式：C57H110N2O6
分子量：919.57
LC-MS:m/z 920[M+H]
1H NMR(DMSO-d6):δ(ppm)4.33(m,2H),4.15(m,2H),3.46(t,1H,J＝3.2Hz),3.35(m,4H),3.20(m,3H),3.10(m,1H),2.97(m,2H),2.62(d,2H,J＝2.1Hz),2.45(m,6H),2.18(m,4H),2.14(d,2H,J＝3.5Hz),1.62(m,6H),1.50(m,6H),1.43(m,8H),1.38(m,8H),1.29(m,10H),1.26(m,36H),0.90(m,12H)。
实例48化合物45的合成
通过类似于实施例1，2，4的合成方法制备得到黄色化合物45
分子式：C56H108N2O6
分子量：905.54
LC-MS:m/z 906[M+H]
1H NMR(DMSO-d6):δ(ppm)4.33(m,2H),4.15(m,2H),3.46(t,1H,J＝3.2Hz),3.35(m,4H),3.20(m,3H),3.10(m,1H),2.97(m,2H),2.62(d,2H,J＝2.1Hz),2.45(m,6H),2.14(d,2H,J＝3.5Hz),1.62(m,10H),1.50(m,2H),1.43(m,8H),1.38(m,6H),1.29(m,10H),1.26(m,36H),0.90(m,12H)。
实例49化合物46的合成
通过类似于实施例1，3的合成方法制备得到黄色化合物46
分子式：C57H104N2O10
分子量：977.46
LC-MS:m/z 978[M+H]
1H NMR(DMSO-d6):δ(ppm)5.14(t,1H,J＝9.55Hz),4.47(m,2H),4.29(t,1H,J＝8.96Hz),4.18(m,2H),3.83(d,2H,J＝5.67Hz),3.57(m,4H),2.97(m,2H),2.69(d,2H,J＝4.23Hz),2.50(m,4H),2.35(m,6H),2.05(m,2H)1.64(m,6H),1.26-1.50(m,58H),0.90(m,12H)。
实例50化合物47的合成
通过类似于实施例1，3的合成方法制备得到黄色化合物47
分子式：C58H107N3O9
分子量：990.51
LC-MS:m/z 991[M+H]
1H NMR(DMSO-d6):δ(ppm)5.14(t,1H,J＝9.55Hz),4.47(m,2H),4.29(t,1H,J＝8.96Hz),4.18(m,2H),3.83(d,2H,J＝5.67Hz),2.97(m,2H),2.69(d,2H,J＝4.23Hz),2.35(m,6H),2.29(m,8H),2.14(s,3H),2.05(m,2H),1.64(m,6H),1.26-1.50(m,58H),0.90(m,12H)。
实例51化合物48的合成
通过类似于实施例1，3的合成方法制备得到黄色化合物48
分子式：C57H106N2O11
分子量：995.48
LC-MS:m/z 996[M+H]
1H NMR(DMSO-d6):δ(ppm)5.14(t,1H,J＝9.55Hz),4.47(m,2H),4.29(t,1H,J＝8.96Hz),4.18(m,2H),4.16(s,2H),3.83(d,2H,J＝5.67Hz),3.42(m,4H),2.97(m,2H),2.69(d,2H,J＝4.23Hz),2.57(m,4H),2.35(m,6H),2.05(m,2H),1.64(m,6H),1.26-1.50(m,58H),0.90(m,12H)。
实例52化合物49的合成
通过类似于实施例1，3的合成方法制备得到黄色化合物49
分子式：C58H106N2O10
分子量：991.49
LC-MS:m/z 936[M+H]
1H NMR(DMSO-d6):δ(ppm)5.14(t,1H,J＝9.55Hz),4.47(m,2H),4.29(t,1H,J＝8.96Hz),4.18(m,2H),4.49(s,2H),3.83(d,2H,J＝5.67Hz),3.60(m,1H),2.97(m,2H),2.69(d,2H,J＝4.23Hz),2.57(m,4H),2.35(m,6H),2.05(m,2H),1.77(m,4H),1.64(m,6H),1.26-1.50(m,58H),0.90(m,12H)。
实例53化合物50的合成
通过类似于实施例1，3的合成方法制备得到黄色化合物50
分子式：C44H83N3O5
分子量：734.27
LC-MS:m/z 735[M+H]
1H NMR(DMSO-d6):δ(ppm)5.14(t,1H,J＝9.55Hz),4.29(t,1H,J＝8.96Hz),4.18(m,2H),3.83(d,2H,J＝5.67Hz),2.97(m,2H),2.69(d,2H,J＝4.23Hz),2.29(m,8H),2.27(m,1H),2.14(m,3H),2.13(m,1H),1.60(m,4H),1.26-1.50(m,48H),0.90(m,12H)。
实例54化合物51的合成
通过类似于实施例1的合成方法制备得到黄色化合物51
分子式：C43H82N2O7
分子量：739.24
LC-MS:m/z 7940[M+H]
1H NMR(DMSO-d6):δ(ppm)5.14(t,1H,J＝9.55Hz),4.29(t,1H,J＝8.96Hz),4.18(m,2H),4.16(s,2H),3.83(d,2H,J＝5.67Hz),3.42(m,2H),2.97(m,2H),2.69(d,2H,J＝4.23Hz),2.57(m,4H),,2.27(m,1H),2.13(m,1H),1.60(m,4H),1.26-1.50(m,48H),0.90(m,12H)。
实例55化合物52的合成
通过类似于实施例1的合成方法制备得到黄色化合物52
分子式：C44H82N2O6
分子量：735.26
LC-MS:m/z 736[M+H]
1H NMR(DMSO-d6):δ(ppm)5.14(t,1H,J＝9.55Hz),4.49(s,1H),4.29(t,1H,J＝8.96Hz),4.18(m,2H),3.83(d,2H,J＝5.67Hz),3.60(m,1H),2.97(m,2H),2.69(d,2H,J＝4.23Hz),2.51(m,4H),,2.27(m,1H),2.13(m,1H),1.77(m,4H),1.60(m,4H),1.26-1.50(m,48H),0.90(m,12H)。
实例56化合物53的合成
通过类似于实施例1,2的合成方法制备得到黄色化合物53
分子式：C55H107N3O8
分子量：938.47
LC-MS:m/z 995[M+H]
1H NMR(DMSO-d6):δ(ppm)8.01(s,1H),4.16(s,2H),4.13(m,4H),3.42(m,2H),3.39(t,1H,J＝3.2Hz),3.35(m,2H),3.30(m,3H),2.69(d,2H,J＝4.23Hz),2.57(m,4H),2.43(m,4H),2.13(m,2H),1.60(m,12H),1.26-1.50(m,52H),0.90(m,12H)。
实例57化合物54的合成
通过类似于实施例1,2的合成方法制备得到黄色化合物54
分子式：C55H104N2O8
分子量：921.44
LC-MS:m/z 922[M+H]
1H NMR(DMSO-d6):δ(ppm)4.18(m,2H),4.13(m,4H),3.57(m,4H),3.39(t,1H,J＝3.2Hz),3.35(m,2H),3.18(t,1H,J＝3.51Hz),2.69(d,2H,J＝4.23Hz),2.50(m,4H),2.43(m,2H),2.13(m,2H),1.60(m,12H),1.26-1.50(m,52H),0.90(m,12H)。
实例58化合物55的合成
通过类似于实施例1,2的合成方法制备得到黄色化合物55
分子式：C56H107N3O7
分子量：934.49
LC-MS:m/z 935[M+H]
1H NMR(DMSO-d6):δ(ppm)4.18(m,2H),4.13(m,4H),3.57(m,4H),3.39(t,1H,J＝3.2Hz),3.35(m,2H),3.18(t,1H,J＝3.51Hz),2.97(m,2H),2.69(d,2H,J＝4.23Hz),2.29(m,8H),2.14(s,3H),2.13(m,2H),1.60(m,12H),1.26-1.50(m,52H),0.90(m,12H)。
实例59化合物56的合成
通过类似于实施例1,2的合成方法制备得到黄色化合物56
分子式：C56H106N2O8
分子量：935.47
LC-MS:m/z 936[M+H]
1H NMR(DMSO-d6):δ(ppm)4.49(s,1H)4.18(m,2H),4.13(m,4H),,3.60(m,1H),3.39(t,1H,J＝3.2Hz),3.35(m,2H),3.18(t,1H,J＝3.51Hz),2.97(m,2H),2.69(d,2H,J＝4.23Hz),2.52(m,4H),2.13(m,2H),1.77(m,4H),1.60(m,12H),1.26-1.50(m,52H),0.90(m,12H)。
实例60化合物57的合成
通过类似于实施例1,2的合成方法制备得到黄色化合物57
分子式：C57H106N2O9
分子量：963.48
LC-MS:m/z 964[M+H]
1H NMR(DMSO-d6):δ(ppm),4.76(d,1H,J＝8.22Hz),4.49(s,1H),4.47(m,1H),4.18(m,2H),4.13(m,2H),3.60(m,1H),3.39(t,1H,J＝3.2Hz),3.35(m,2H),3.18(t,1H,J＝3.51Hz),2.97(m,2H),2.71(d,2H,J＝4.23Hz),2.52(m,4H),2.32(m,4H),2.13(m,1H),1.77(m,4H),1.64(m,4H),1.60(m,6H),1.26-1.50(m,50H),0.90(m,12H)。
实例61化合物58的合成
通过类似于实施例1,2的合成方法制备得到黄色化合物58
分子式：C57H106N3O8
分子量：963.48
LC-MS:m/z 936[M+H]
1H NMR(DMSO-d6):δ(ppm),4.76(d,1H,J＝8.22Hz),,4.47(m,1H),4.18(m,2H),4.13(m,2H),3.39(t,1H,J＝3.2Hz),3.35(m,2H),3.18(t,1H,J＝3.51Hz),2.97(m,2H),2.71(d,2H,J＝4.23Hz),2.32(m,4H),2.29(m,8H),2.14(s,3H),2.13(m,1H),1.64(m,4H),1.60(m,6H),1.26-1.50(m,50H),0.90(m,12H)。
实例62化合物59的合成
通过类似于实施例1,2的合成方法制备得到黄色化合物59
分子式：C56H104N2O9
分子量：949.45
LC-MS:m/z 950[M+H]
1H NMR(DMSO-d6):δ(ppm),4.76(d,1H,J＝8.22Hz),,4.47(m,1H),4.18(m,2H),4.13(m,2H),3.57(m,4H),3.39(t,1H,J＝3.2Hz),3.35(m,2H),3.18(t,1H,J＝3.51Hz),2.97(m,2H),2.71(d,2H,J＝4.23Hz),2.50(m,4H),2.32(m,4H),2.14(s,3H),2.13(m,1H),1.64(m,4H),1.60(m,6H),1.26-1.50(m,50H),0.90(m,12H)。
实例63化合物60的合成
通过类似于实施例1,2的合成方法制备得到黄色化合物60
分子式：C52H107N3O9
分子量：966.54
LC-MS:m/z 967[M+H]
1H NMR(DMSO-d6):δ(ppm),4.76(d,1H,J＝8.22Hz),,4.47(m,1H),4.16(s,2H),4.13(m,2H),3.42(m,2H),3.39(t,1H,J＝3.2Hz),3.35(m,2H),3.30(m,2H),3.18(t,1H,J＝3.51Hz),2.71(d,2H,J＝4.23Hz),2.46(m,2H),2.32(m,4H),2.14(s,3H),2.13(m,1H),1.64(m,4H),1.60(m,6H),1.26-1.50(m,50H),0.90(m,12H)。
实施例64
利用脂质纳米颗粒组合物的荧光素酶mRNA体内评价
将阳离子脂质、DSPC、胆固醇和PEG-脂质以50:10:38:2或48:10:40:2的摩尔比溶解在乙醇中。以约10:1至30:1的总脂质与mRNA的重量比制备脂质纳米颗粒(LNP)。简而言之，将mRNA在10mL至50mL柠檬酸盐缓冲液(pH＝4)稀释至0.15mg/mL。使用注射器泵，将脂质的乙醇溶液与mRNA水溶液以约1:5至1:3(体积/体积)的比例混合，总流速为10mL/min以上。然后去除乙醇，并通过透析用PBS替代外部的缓冲液。最后，将脂质纳米颗粒通过0.2μM孔径的无菌过滤器过滤。使用Malvern Zetasizer Nano ZS通过准弹性光散射测定的脂质纳米颗粒的粒径为直径大约65-105nm，并且在一些情况下，直径大约75-100nm。
根据国家科学技术委员会制定的指南，在6-8周龄的雌性C57BL/6小鼠，8-10周龄CD-1小鼠上进行研究。通过尾静脉注射全身性给予不同剂量的mRNA脂质纳米颗粒，并在给药后的特定时间点(例如5小时)使动物安乐死。将肝脏和脾脏收集在预先称重的管中，确定重量，立即在液氮中快速冷冻，并且在-80℃下储存，直至用于分析。
对于肝脏，切割约50mg以便在2mL FastPrep管(MP Biomedicals，Solon OH)中进行分析。向各个管中加入1/4"陶瓷球(MP Biomedicals)，并将平衡至室温的500μL的Glo裂解缓冲液-GLB(Promega，Madison WI)加入到肝脏组织中。使用FastPrep24仪器(MPBiomedicals)将肝脏组织在2x6.0 m/s下均匀化15秒。将匀浆在室温下孵育5分钟，然后在GLB中进行1:4稀释，并使用SteadyGlo荧光素酶测定系统(Promega)进行评估。具体地，将50μL的稀释的组织匀浆与50μL的SteadyGlo底物反应，摇振10秒，接着孵育5分钟，然后使用SpectraMAX_L化学发光型酶标仪(美谷分子仪器(上海)有限公司)定量。通过使用BCA蛋白质定量试剂盒(上海易色医疗科技有限公司)来确定测定的蛋白质的量。然后将相对发光度单位(RLU)归一化成所测定蛋白质的总μg。为了将RLU转化成μg荧光素酶，用QuantiLum重组荧光素酶(Promega)生成了标准曲线。
来自Trilink Biotechnologies的FLuc mRNA(L-6107)将表达荧光素酶蛋白，其最初从萤火虫(Photinus pyralis)中分离出来。Fluc通常用于哺乳动物细胞培养物中以测量基因表达和细胞活力。其在底物萤光素存在下发射出生物性光。这种加帽并且聚腺昔酸化的mRNA被5-甲基胞苷和假尿苷完全取代。
实施例65
所配制得脂质的pKa的测定
所配制的阳离子脂质的pKa与用于递送核酸的LNP的效果相关。优选的pKa范围是5～7。使用基于2-(对甲苯胺基)-6-荼磺酸(TNS)的荧光的分析，在脂质纳米颗粒中测定各阳离子脂质的pKa。如实施例64中所述，使用有序的方法来制备在PBS中的浓度为0.4mM总脂质的包含阳离子脂质/DSPC/胆固醇/PEG脂质(50/10/38/2mol％)的脂质纳米颗粒。将TNS在蒸馏水中制备成100μM储备溶液。将囊泡稀释成在2mL缓冲溶液中含24μM脂质，所述缓冲溶液含有10mM HEPES、10mM MES、10mM乙酸按、130mM NaCl，其中pH值为2.5～11。加入等份的TNS溶液以产生1μM的终浓度，并且在涡旋混合之后，在室温下使用321nm和445nm的激发波长和发射波长在SLM Aminco Series 2发光分光光度计中测量荧光强度。对荧光数据应用S形最佳拟合分析，并将pKa测量为产生半数最大荧光强度的pH。
实施例66
使用体内荧光素酶mRNA表达的啮齿动物模型测定含有各种阳离子脂质的脂质纳米颗粒制剂的效能
为了比较的目的，如实施例64所述，使用有序混合方法，将这些脂质也用于配制含有FLuc mRNA(L-6107)的脂质纳米颗粒。使用以下摩尔比来配制脂质纳米颗粒:50％阳离子脂质/10％二硬脂酰磷脂酰胆碱(DSPC)/38％胆固醇/2％PEG脂质("PEG-DMG"，即，(1-(单甲氧基一聚乙二醇)-2,3一二肉豆蔻酰基甘油，平均PEG分子量为2000)。如实施例64所述，在经由尾静脉注射施用之后的5小时，通过测量肝脏中的荧光素酶表达来确定相对活性。在0.3和1.0mg mRNA/kg的剂量下比较所述活性，并表达成在如实施例64所述的施用之后5小时测量的ng荧光素酶/g肝脏。实施例64及65结果如表2所示。
表2与mRNA表现出活性的比较脂质
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对公开专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
Claims (19)
1.一种如式A所示的吡咯烷类化合物，或其异构体、或其N-氧化物、或其药学可接受的盐、前药；
其中：
L1选自以下结构：-C-、-O(C＝O)-、-(C＝O)O-、-C(＝O)-、-O-、-S(O)X-、-S-S-、-C(＝O)S-、-SC(＝O)-、-N-C(＝O)-、-C(＝O)-N-，L2选自以下结构：-C-、-(C＝O)O-、-C(＝O)-、-S(O)X-、-C(＝O)S-、-C(＝O)-N-；
R1和R2各自独立地为C6-C24烷基或C6-C24烯基，所述的烃基链任意的被一个或多个酯键或醚键连接；
R3和R4各自独立地为C1-C12烷基或C1-C12烯基，或R3和R4彼此结合形成4至10元杂环，所述杂原子包括N、O、S中的一种或多种杂原子，所述杂环任选地被1-6个杂原子取代；
X为C、N、O、S、-S-S-；
M为C1-C12烷基或C1-C12烯基；
x为0、1或2。
2.如权利要求1所述的化合物，其中L1为-O(C＝O)-或-O-中的一种，L2为-C-或-C(＝O)-中的一种。
3.如权利要求1所述的化合物，其特征在于：其中R1和R2或两者具有以下结构之一：
4.如权利要求1所述的化合物，其中X为N或O，M为C1-C6烷基。
5.其特征在于：其中M-N(R3)(R4)具有以下结构之一：
6.一种权利要求1-5任一项所述的吡咯烷类化合物A的制备方法，其包括下列步骤：
(1)在有机溶剂中，在缚酸剂或缩合剂作用下，化合物H与通式化合物G进行取代/缩合反应，制得通式中间体F；
(2)在有机溶剂中，在缩合剂作用下，通式中间体F与通式化合物E进行缩合反应，制得通式中间体D；
(3)在有机溶剂中，在酸催化作用下，通式中间体D进行脱保护反应，制得通式中间体C；
(2)在有机溶剂中，在缚酸剂和缩合剂作用下，通式中间体C与通式化合物B进行取代/缩合反应，制得通式A的吡咯烷类化合物；
7.包含上述权利要求中任一项所述的化合物和治疗剂的组合物。
8.如权利要求7所述的组合物，其还包含选自中性脂质、类固醇以及聚合物脂质中的一种或多种组分。
9.如权利要求8所述的组合物，其中所述中性脂质包含DSPC、DPPC、DMPC、DOPC、POPC、DOPE和SM中的一种或多种组分，较优的为DSPC。
10.如权利要求7-9中任一项所述的组合物，其中所述化合物和所述中性脂质的摩尔比为约2:1至8:1。
11.如权利要求7-10中任一项所述的组合物，其中所述类固醇包含胆固醇、粪固醇、谷固醇、麦角固醇、菜油固醇、豆固醇、菜籽固醇中的一种或多种，较优的为胆固醇。
12.如权利要求11所述的组合物，其中所述化合物和类固醇的摩尔比为约1:1至5:1。
13.如权利要求7-12中任一项所述的组合物，其中所述聚合物脂质为聚乙二醇化脂质，其包含PEG-DAG、PEG-PE、PEG-S-DAG、PEG-cer或PEG-二烷氧基丙基氨基甲酸酯。
14.如权利要求13中所述的组合物，其中所述聚乙二醇化脂质具有以下结构(I)：
或其异构体、药学可接受的盐、前药，其中：
R7和R8各自独立地为含有10至30个碳原子的直链或支链的、饱和或不饱和的烃基链，其中所述的烃基链任意的被一个或多个酯键连接；
w为30至60的平均值。
15.如权利要求14所述的组合物，其中R7和R8各自独立地为含有12至22个碳原子的直链、饱和或不饱和的烃基链。
16.如权利要求7-15中任一项所述的组合物，其中所述治疗剂为核酸。
17.如权利要求16中任一项所述的组合物，其中所述核酸选自反义核酸、小干扰核酸(siRNA)、微小核酸(miRNA)和信使核酸(mRNA)。
18.如权利要求7-17中任一项所述的组合物在制备用于治疗如下疾病药物或疫苗中的应用，所述疾病包含感染性疾病、癌症和增生性疾病、遗传病、自身免疫性疾病、神经退化性疾病、心血管和肾血管疾病及代谢性疾病。
19.如权利要求7-18中任一项所述的组合物，向患者施用的给药途径包含：静脉内、肌肉内、皮下、皮内、鼻内或吸入给药。
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